8-6532368-C-A

Variant names:

• chr8-6532368-C-A
• rs6559167
• NM_001118887.2:c.408G>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001118887.2(ANGPT2):​c.408G>T​(p.Ala136Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,613,718 control chromosomes in the GnomAD database, including 78,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A136A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.29 (6737 hom., cov: 30)
  • Exomes 𝑓: 0.31 (71562 hom.)
• Consequence: ANGPT2 NM_001118887.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.49
• Publications: 19 publications found

Genes affected

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-6532368-C-A is Benign according to our data. Variant chr8-6532368-C-A is described in ClinVar as Benign. ClinVar VariationId is 158839.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.408G>T	p.Ala136Ala	synonymous_variant	Exon 2 of 9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2214+32439C>A		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.408G>T	p.Ala136Ala	synonymous_variant	Exon 2 of 9	1	NM_001118887.2	ENSP00000486858.2
MCPH1	ENST00000344683.10	c.2214+32439C>A		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44577 AN: 151794 Hom.: 6737 Cov.: 30

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.300 AC: 75368 AN: 251380 AF XY: 0.302

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.400

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.310 AC: 453601 AN: 1461806 Hom.: 71562 Cov.: 63 AF XY: 0.310 AC XY: 225351 AN XY: 727206

African (AFR) AF: 0.237 AC: 7933 AN: 33476

American (AMR) AF: 0.262 AC: 11711 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8564 AN: 26134

East Asian (EAS) AF: 0.418 AC: 16594 AN: 39694

South Asian (SAS) AF: 0.252 AC: 21719 AN: 86240

European-Finnish (FIN) AF: 0.280 AC: 14946 AN: 53410

Middle Eastern (MID) AF: 0.355 AC: 2050 AN: 5768

European-Non Finnish (NFE) AF: 0.316 AC: 351306 AN: 1111970

Other (OTH) AF: 0.311 AC: 18778 AN: 60394

GnomAD4 genome AF: 0.293 AC: 44580 AN: 151912 Hom.: 6737 Cov.: 30 AF XY: 0.291 AC XY: 21597 AN XY: 74236

African (AFR) AF: 0.241 AC: 9985 AN: 41408

American (AMR) AF: 0.288 AC: 4401 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1114 AN: 3466

East Asian (EAS) AF: 0.403 AC: 2075 AN: 5152

South Asian (SAS) AF: 0.233 AC: 1118 AN: 4804

European-Finnish (FIN) AF: 0.285 AC: 3013 AN: 10554

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21827 AN: 67936

Other (OTH) AF: 0.327 AC: 692 AN: 2114

Alfa AF: 0.304 Hom.: 2252

EpiCase AF: 0.333

EpiControl AF: 0.326

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.051
DANN	Benign	0.75
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6559167; hg19: chr8-6389889; COSMIC: COSV57337589;